# Sex-specific regulation of microRNAs in Alzheimer Disease

> **NIH NIH R01** · LOYOLA UNIVERSITY CHICAGO · 2024 · $653,367

## Abstract

PROJECT SUMMARY
Alzheimer’s Disease is more prevalent in women than men, yet a biological basis for this sex difference is not
understood. The primary objective of this proposal is to understand how 17β-estradiol (E2) regulates microRNA
(miR) biogenesis and stability across the lifespan and in Alzheimer’s Disease (AD). We hypothesize that
dysregulation of E2-mediated miR expression in the aged brain leads to greater Alzheimer Disease risk in
women. The studies proposed are focused on understanding how estrogens regulate these miRs to get a
better understanding of their dysregulation in AD - specifically in women. This will address a major gap in our
understanding because how E2 influences the components of the miR biogenesis pathway to regulate mature
miR expression levels in a cell- and/or age-specific manner is unknown, despite several studies demonstrating
temporal and cell-specific effects of E2 on miR expression in a variety of organ systems. Our prior studies
demonstrated that E2 treatment altered the expression levels of a subset of miRs in the female brain, and the
ability to regulate these miRs depended on age, brain region, and length of E2 deprivation (i.e., time post-
menopause). Collectively the experiments in Aim 1 will test the hypothesis that E2 differentially mediates
mature miR stability depending on age and in Alzheimer’s Disease. We will use miR degradation assays to
determine whether age and/or E2 affect the rate of miR degradation and, using a proteomics approach, identify
the cis- and trans-acting factors that regulate miR stability. Aim 2 will addresses mechanistically how a select
subset of miRs could be specifically regulated by E2 post-transcription. We will test the hypothesis that hnRNP
H binding to ERβ reduces its association with pri-miR transcripts, ERβ interacts with BRCA1 to differentially
facilitate DROSHA complex assembly, and that these interactions are dependent on age and E2 treatment.
Aim 3 will determine the effects of age and E2 on miR subcellular localization and assess disruption of E2-
mediated miR subcellular localization in Alzheimer’s Disease. This aim will test the hypothesis that E2 facilitates
subcellular trafficking of miRs, thereby impacting miR function. Moreover, we will test the hypothesis that miR
subcellular localization changes across the lifespan and that normal age-related subcellular localization is
disrupted in Alzheimer’s Disease. Impact: Understanding the basic molecular signaling pathways of E2 in the
aging brain will help drive therapeutic advances and inform treatment strategies for women with Alzheimer’s
Disease.

## Key facts

- **NIH application ID:** 10825616
- **Project number:** 5R01AG082135-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Toni R. Pak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $653,367
- **Award type:** 5
- **Project period:** 2023-04-15 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825616

## Citation

> US National Institutes of Health, RePORTER application 10825616, Sex-specific regulation of microRNAs in Alzheimer Disease (5R01AG082135-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825616. Licensed CC0.

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